The ability of the liver to recover from toxic, infectious or inflammatory injury and following liver transplantation is due in large part to the ability of quiescent (GO), metabolically active hepatocytes to reenter the cell cycle en masse. Hepatocyte reentry into the cell cycle and genomic integrity are critically dependent on E2F regulated activation of DNA replication licensing factors. TGF-a induces hepatocyte proliferation in physiologic growth and in the preneoplastic stages of hepatocellular carcinoma. We have identified C/EBP[unreadable] as a key transcriptional activator of E2F-regulated genes that control the licensing of DNA replication during hepatocyte proliferation. We have shown that induction of C/EBP[unreadable]-dependent induction of DNA replication factors is both stimulated by TGF-a and dependent on C/EBP[unreadable] in primary hepatocytes. Recent evidence has identified an important link between the metabolic state and activation of cell cycle associated genes including those regulated by E2F factors. We have discovered that the potential coactivator PGC-1a, previously implicated in the response to fasting, is rapidly induced following partial hepatectomy in a C/EBP[unreadable]-dependent manner and is bound to the promoters of E2F regulated genes including several C/EBP[unreadable] targets, suggesting that this coactivator is an important link between metabolic signals and hepatocyte proliferation. Based on data from our laboratory and others, we hypothesize that C/EBP[unreadable] is a central integrator of growth factor and metabolic signals to hepatocytes. In Specific Aim 1, we will investigate the contribution of C/EBP[unreadable] phosphorylation and C/EBP[unreadable]-E2F interactions for regulation of DNA licensing proteins during hepatocyte proliferation. In Specific Aim 2, we will investigate the mechanism for activation of PGC-1a by C/EBP[unreadable]. In Specific Aim 3, we will analyze the functional role of PGC-1a in hepatocyte proliferation in the regenerating liver. This grant application is directly responsive to Program announcement PA-06-231. "Developmental Biology and Regeneration of the Liver." Understanding the mechanisms underlying hepatocyte proliferation will inform the development of therapeutics to augment the regenerative capacity of the liver and will elucidate mechanisms of abnormal hepatocyte proliferation that occur during early stages of hepatocellular carcinogenesis.